In this nested case–control study of the association between serum IgE and glioma, the largest study to our knowledge conducted to date in this area, we found that elevated levels of prediagnostic allergen-specific IgE and total IgE are associated with reduced risk of both glioblastoma and glioma. However, the association between testing positive for allergen-specific IgE and decreased tumor risk was restricted to women. Furthermore, we observed that the association with elevated total IgE was present at least 20 years before tumor diagnosis for both sexes combined. In addition, our findings suggest that for both sexes combined, the simultaneous presence of elevated levels of both allergen-specific IgE and total IgE may be associated with a lower risk of glioblastoma and glioma than are negative levels for both types of IgE; however, it should be noted that these associations are only of borderline significance.
In a nested case–control study, Calboli et al. (14
) reported no association between allergen-specific IgE concentration and glioma risk. However, our findings are remarkably similar to those reported by Schlehofer et al. (13
) for high-grade (anaplastic astrocytoma and glioblastoma) glioma. We found sex-specific differences for associations between testing positive for allergen-specific IgE and glioblastoma compared with testing negative (>0.35 kUA
/L vs ≤0.35 kUA
/L: women, OR = 0.46, 95% CI = 0.23 to 0.93; men, OR = 1.02, 95% CI = 0.72 to 1.44) (13
). Schlehofer et al. (13
) found approximately the same magnitude of sex-specific differences for the association between allergen-specific IgE and high-grade glioma: women—OR = 0.45, 95% CI = 0.21 to 0.96; men—OR = 0.90, 95% CI = 0.53 to 1.51. We found a similar, if somewhat weaker, pattern for all glioma, which is also similar to the findings by Schlehofer et al. (13
). The reason for sex-specific variation of the association between allergen-specific IgE and risk of glioblastoma and glioma risk is not known. Female sex hormones have a complex association with allergy-induced inflammation (24
). For example, it has recently been determined that mast cells have estrogen receptors (26
). However, Michaud et al. (27
) reported results of a cohort study in which they found no evidence for an association between reproductive factors and the risk of glioma.
Total IgE levels among control subjects in the present study are consistent with those reported in the study by Calboli et al. (14
). They observed a mean value of the logarithm of total IgE among control subjects of 3.34 (SD = 1.91), whereas the mean value in the present study is 3.35 (SD = 1.27). However, these authors found no association between testing positive for total IgE and risk of glioma compared with testing negative (>100 kU/L vs ≤ 100 kU/L, OR = 0.98, 95% CI = 0.61 to 1.56). Although they did report a statistically significantly decreased risk of glioma for borderline IgE concentration compared with normal concentration (25–100 kU/L vs <25 kU/L: OR = 0.63, 95% CI = 0.42 to 0.93), we were unable to confirm this.
Our most important finding is that testing positive for total IgE was associated with decreased glioblastoma and glioma risk at least 20 years before diagnosis. This observation suggests that previously reported case–control associations between allergy and glioma may not be a consequence of immune suppression resulting from the preclinical tumor. Although the most common form of glioblastoma appears to arise rapidly de novo (28
), our findings indicate that the genesis of this tumor may be a long process.
Our findings also suggest a joint association between allergen-specific and total IgE, and there is evidence that indicates a biological relationship between these two IgE types. Christensen et al. (6
) report that the same concentrations of allergen-specific IgE vary in their ability to produce mast cell activation, depending on the characteristics of the antigen and the relative quantity of total IgE. Consistent with this observation, Hamilton and Williams (28
) report that the larger the ratio of allergen-specific IgE to total IgE, the more likely the induction of inflammatory mediators.
This study has several limitations including the fact that serum samples on which we base our analyses have been stored at −25°C for as long as 39 years (median time between blood collection and IgE analysis = 26 years, interquartile range = 22–36 years). Whether individual values for IgE are the same as they would have been at the date that blood was collected cannot be determined. However, Henderson et al. (29
) tested the stability of IgE levels in obstetric sera that had been stored at −20°C for between 32 and 37 years and found that long-term storage did not diminish the ability to measure IgE levels. A study of the stability of total IgE in the Janus Serum Bank suggested nonstatistically significant (P
> .05) mean differences in serum concentration depending on storage time (30
); however, there may be secular trends in IgE concentration, making it difficult to interpret comparisons across time. Paganelli et al. (31
) also confirm the relative stability of allergen-specific antibodies after 8 years of sample storage. Furthermore, even if there were some degradation of antibodies over time because samples were matched on date of blood collection, both case subjects and control subjects would be similarly affected by serum degradation and secular trends, thus potentially producing nondifferential misclassification. This form of bias usually, but not always, causes the odds ratio to be closer to the null than it should otherwise be (32
). Another potential source of misclassification is that we measured IgE concentration at only one time. The nature of the resulting bias depends on the critical time of IgE exposure that is associated with the risk of glioma, which is unknown. However, it seems reasonable to assume that IgE measurements in case and control subjects would be similarly biased, thus producing nondifferential misclassification. However, if IgE levels of case subjects are altered by proximity to diagnosis of this immune-suppressive tumor, then differential misclassification, resulting in falsely increased or decreased associations, may be present. This bias, if it exists, would be stronger among samples collected near the time of diagnosis.
Consistent with our finding that total IgE was associated with decreased risk of glioma is that total IgE maintains mast cell homeostasis (33
) and mast cells have immunosuppressive functions (34
). Additional evidence for a regulatory role of total IgE is based on the observation that corticosteroids that suppress chronic allergic inflammation paradoxically increase total IgE levels (35
). For example, dexamethasone, a glucocorticoid used to reduce intracranial swelling in glioma patients, also elevates total IgE levels (36
). Although this phenomenon has been discussed as a potentially adverse effect of steroid use for asthma treatment, elevated total IgE may be a component of the mechanism by which glucocorticoids regulate allergic inflammation.
Not necessarily in conflict with an immune regulatory role of total IgE, the reduced risk of cancer among people with allergies has been attributed to immune surveillance against potentially cancerous cells (37
). It may be that the higher levels of circulating IgE in atopic individuals provide an enhanced capability to eradicate premalignant cells before tumors can be detected. This antitumor protection could be due to IgE specific for developing tumors, to nonspecific IgE with cross-reactivity to nascent tumor antigens, or immune mediators released by the binding of IgE to specific receptors on effector cells. Another possible scenario is that of immune prophylaxis (9
), in which allergy symptoms themselves, triggered by IgE, serve to expel foreign toxins or pathogens that might be mutagenic. Regardless of the mechanism, experimental evidence indicates that circulating IgE may impede early tumor development (37
The third potential narrative comes from a prospective Danish record linkage study of contact allergy (5
), a type of allergy that causes delayed rather than immediate hypersensitivity and involves T cells exclusively and not IgE. In the cohort of people diagnosed with contact allergy, the authors found that women, but not men, previously treated for this allergy had a lower risk of primary brain tumors. This finding does not exclude a role for IgE, however, because T cells are also involved in the induction of IgE-induced immediate hypersensitivity.
In addition to finding associations between both allergen-specific and total IgE and glioma risk, we are first to observe the presence of this association long before tumor diagnosis. Furthermore, we found that allergen-specific and total IgE may be simultaneously related to glioblastoma and glioma risk. If our findings can be replicated, basic research is needed to identify biological mechanisms that account for the observed associations. Whether this mechanism represents a form of immune surveillance or is a correlate of serum IgE concentration remains to be determined.